Bone destruction is a hallmark of multiple myeloma (MM), a largely incurable B-cell malignancy that affects more than 14,400 Americans annually. Over 80% myeloma patients develop osteolytic bone lesions that can cause pathological fractures and severe bone pain. Our previous study showed that C-reactive protein (CRP), the first acute-phase protein described and a prognostic indicator for MM and other cancers, enhances myeloma cell proliferation under stressed conditions and protects myeloma cells from chemotherapy drug-induced apoptosis in vitro and in vivo. CRP binds activating Fc? receptors, activates PI3K/Akt, ERK, and NF-?B pathways and inhibits caspase cascade activation induced by chemotherapy drugs. CRP also enhanced myeloma cell secretion of IL-6 and synergized with IL-6 to protect myeloma cells from chemotherapy drug-induced apoptosis (Yang et al., Cancer Cell 2007;12:252). Our recent studies have further suggested that CRP may also be involved in myeloma bone disease. We have shown that CRP-producing, but not the unmanipulated or control vector-transduced myeloma cell lines produce osteolytic lesions in both murine and human bones in SCID and SCID-hu mice. Our in vitro studies further showed that, compared with the wild-type or control vector-transduced cells, these two cell lines produced significantly higher levels of receptor activator of nuclear factor ?B ligand (RANKL), TNF-a, and dickkopf-1 (DKK1). Addition of CRP also stimulated myeloma cells (cell lines and primary myeloma cells from patients) to secrete these cytokines. As RANKL and TNF-a are required for osteoclast (OC) differentiation and activity, and DKK1 is an osteoblast (OB) differentiation inhibitor, the central hypothesis of this project is that CRP may play an active role in osteolytic bone destruction in MM via affecting OC and OB differentiation and activity. In this project, we will examine the role of CRP on OC and OB differentiation and activity in vitro (aim 1), examine the mechanism of CRP-mediated bone destruction and develop strategies to counteract the effects of CRP on bones in vivo (aim 2), and examine and validate the role of CRP in bone destruction in patients with MM (aim 3). These novel studies are scientifically innovative and important, and highly significant for the treatment of MM and its associated bone disease.